computational search for long bonds in radical cations of sugars 1

FARMACIA, 2016, Vol. 64, 4

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ORIGINAL ARTICLE

COMPUTATIONAL SEARCH FOR LONG BONDS IN RADICAL CATIONS OF SUGARS 1. GLUCOFURANOSE, GALACTOFURANOSE AND MANNOFURANOSE DI-O-ISOPROPYLIDENE DERIVATIVES MIHAI-COSMIN PASCARIU1, MADIAN RAFAILĂ2, MIHAI MEDELEANU2, VALENTIN BADEA2, ALEXANDRA TEODORA GRUIA3, VICTOR LORIN PURCAREA4, MIRCEA PENESCU4,5, EUGEN SISU6*

1“Vasile Goldiş” Western University of Arad, Faculty of Pharmacy, 86 Liviu Rebreanu, 310045, Arad, Romania 2University Politehnica Timişoara, Faculty of Industrial Chemistry and Environmental Engineering, 6 Carol Telbisz, 300001, Timişoara, Romania 3Clinical County Hospital of Timișoara, Immunology of Transplant Department, 10 Iosif Bulbuca Blvd., 300736, Timişoara, Romania 4“Carol Davila” University of Medicine and Pharmacy, 37 Dionisie Lupu, 020021, Bucharest, Romania 5“Carol Davila” Hospital of Nephrology, 4 Calea Griviței, 010731, Bucharest, Romania 6“Victor Babeş” University of Medicine and Pharmacy of Timișoara, Faculty of Medicine, 2 Eftimie Murgu Sq., 300041, Timișoara, Romania *corresponding author: [email protected]

Manuscript received: June 2015 Abstract

The di-O-isopropylidene derivatives of aldohexoses, in their furanose form, are easily recognized during positive mode electron ionization mass spectrometry analysis because they all exhibit a strong intensity peak at m/z 101, which is usually the base peak. The literature data indicate that this peak appears due to the 2,2-dimethyl-1,3-dioxolan-4-ylium ion, which is formed through the detachment of the exocyclic dioxolane acetal. In the molecular ion, the radical character seems to be localized at the conjunction between the exocyclic dioxolane acetal and the furanose hemiacetal, the carbon-carbon bond between the two rings thus gaining a long bond character. We have used semi-empirical calculations to prove that such long bonds represent a rational explanation for the genesis of the m/z 101 cation in diastereomeric hexofuranose diacetals and their alkyl derivatives. The theoretical results seem to confirm the conclusions resulted from the analysis of mass spectra acquired for a series of furanose compounds. Rezumat

Derivații di-O-izopropilidenici ai aldohexozelor în formă furanozică sunt ușor de recunoscut la analiza prin spectrometrie de masă cu ionizare electronică în modul ion pozitiv prin faptul că prezintă un pic de intensitate mare la valoarea m/z 101, în majoritatea cazurilor acesta reprezentând picul de bază. Literatura atribuie această valoare ionului de fragmentare 2,2-dimetil-1,3-dioxolan-4-iliu, format prin detașarea acetalului dioxolanic exociclic. Caracterul radicalic în ionul molecular pare a fi localizat la conjuncția dintre acetalul dioxolanic exociclic și hemiacetalul furanozic, legătura carbon-carbon dintre cele două cicluri dobândind astfel un caracter de „legătură lungă‟. Pentru a dovedi că asemenea legături lungi constituie o explicație rațională pentru generarea cationului de la m/z 101 în diacetali de hexofuranoze diastereoizomere și derivați alchilați ai acestora, s-au utilizat calcule semi-empirice. Rezultatele teoretice par să confirme concluziile ce rezultă din analiza spectrelor de masă achiziționate pentru o serie de derivați furanozici. Keywords: diacetone derivatives, hexofuranoses, radical cation, oxocarbenium ion, long bond, semi-empirical quantum chemistry methods, mass spectrometry, GC-EI-MS Introduction

The carbohydrates, also known as saccharides, are oxygen-rich compounds, widely spread in nature and with critical importance for living systems. Due to the fact that they are involved in a variety of fundamental biological processes and pathological situations, carbohydrates have a large pharmaceutical and diagnostic potential [1]. These species and also

their derivatives can be found in both drugs (e.g., aminoglycosides) and excipients (e.g. biocompatible surfactants, like long chain glycoderivatives) [2-4]. Among analytical methods which offer plentiful and reliable information regarding the structural details of carbohydrates, mass spectrometry is regarded as a top choice method. These compounds can be analysed in either positive or negative operating modes. With the introduction of modern


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mass spectrometry techniques (MS/MS or tandem MS) the isolation of fragments from the primary spectrum became possible. These fragments can be further subjected to collision fragmentation (collision-induced dissociation (CID-MS)), producing the MS2 spectrum [5-11]. Nonetheless, when the sugar derivative structure allows for electron impact ionization mass spectrometric analysis, information-rich EI-MS spectra are obtained. The parent structure can then be determined from analysing the fragment ions, specifically the cations or the radical cations, if positive ionization is employed. Their abundance can be correlated with their stability, and the diverse electronic or steric effects can give strong information for the predominance of a certain fragmentation path over another [12]. When two fragmentation pathways seem to have equal probabilities, one can invoke quantum chemical or semi-empirical calculations for additional data [5, 13, 14]. Molecular modelling based on such calculations is also widely used for (Q)SAR studies which lead to new drug design [15-18]. On the other hand, one can naturally speculate that in the molecular radical cation, which is born in the electronic impact event, the positive charge does not distribute itself evenly on all the atoms and thus some bonds will be affected more than others. The more labile bonds will exhibit a greater interatomic distance and thus the fragmentation probability in that specific position will increase [14]. This phenomenon was previously observed, for example, in 1,2-disubstituted derivatives of ethane [19, 20]. Alkane radical cations [14, 21] were theoretically predicted to possess an elongated, one-electron C-C bond [14, 19, 20, 22-31]. In the case of ethane radical cation, for example, calculations established its optimum length to be 1.920 Å, with a bond dissociation energy (BDE) of 43 kcal/mol [19]. More complex alkane radical cations also present one such long bond in which the single occupied molecular orbital (SOMO) and the “radical cation character” are rather highly localized [19, 20, 25, 32-40] (although some other studies contradict the long bond structure as the ground state for the ethane [22, 41-44] or for the propane radical cation [45]). Theoretical investigation has further suggested that the ground state long bond structures may also be found for radical cations of alcohols, ethers and halocarbons [19, 20, 46-53]. Moreover, ab initio studies show a unique stabilizing effect of vicinal electron donor substituents on long bond radical cation structures [19, 54-60] (Figure 1). Although at first it would appear that the radical cation character is largely localized on the easily ionisable functionality (containing, for example, nitrogen or oxygen), the calculated structural minimum is instead a long bond structure, with the long bond maintaining substantial

bond strength (i.e., it possesses a fairly good BDE). Known examples are ethylenediamine radical cation (2.030 Å, BDE = 22.6 kcal/mol), whose long bond structure lies 11.2 kcal/mol below the best localized (aluminium ion) structure, and ethylene glycol (2.048 Å, BDE = 23.6 kcal/mol) [19].

Figure 1. The stabilization of radical cations in vicinal

compounds [19] The electron ionization – mass spectrometry (EI-MS) spectra of compounds such as ethylene-diamine, ethylene glycol and 1,2-dimethoxyethane seem to support the formation of such a long bond in the molecular radical cation. All three spectra show a preference for a symmetric breaking of their structures, giving base peaks at a value which is half the molecular mass [61]. Using GC-EI-MS analysis and computational chemistry we have proposed in a previous paper, a qualitative distinction between sugar anomers (as long chain derivatives which could find applications as biocompatible and biodegradable surfactant precursors in fields like pharmaceuticals or bio-chemistry) [62].

Figure 2. The genesis of the 2,2-dimethyl-1,3-dioxolan-4-ylium

cation; the true orientation of the wavy bond is given for each series of compounds (Glc - glucose,

Gal - galactose, Man - mannose base structure) In this study, we further investigated a series of related di-O-isopropylidene furanose radical cations, which included glucose (Glc), galactose (Gal) and mannose (Man) derivatives. These were generated from the corresponding neutral molecules during positive


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mode EI-MS experiments, and also theoretically analysed with the RM1 (Recife Model 1) semi-empirical quantum chemical method. The findings confirm and explain the mode of cleavage which leads to the abundant m/z 101 ionic fragment [62-67] in the EI-MS analysis of these sugar acetals (Figure 2). Materials and Methods

The analysed compounds can be prepared by chemo-selective bis-acetalation of d-glucose/d-galactose/d-mannose with acetone in acidic media (compounds in which R = H, see Figure 2) [68, 69], followed by either 1,4-dibromobutane (R = C4Br) and then 1-octanol/1-decanol, or by mesylated octyloxybutanol/ decyloxybutanol (R = C4OC8 / C4OC10), both of these routes taking place in alkaline organic media. Dehydrohalogenation of bromobutyl (R = C4Br) derivatives occurs in the reaction conditions, leading to butenyl (R = C4) derivatives. The synthesis of these products was described in a previous work [70]. The GC-EI-MS analyses parameters were also described elsewhere [62]. The EI-MS spectra were collected for analysis from the highest point of the chromatographic peak. All structures were processed using HyperChem software [71]. The starting neutral molecules were pre-optimized with the OPLS force field and optimized with the RM1 semi-empirical method [72]. The radical cations (formal charge “+1”, spin multiplicity

“2”) were obtained from these structures and were finally optimized with the RM1 semi-empirical method, with and without using molecular mechanics. The force fields used for this purpose include MM+, AMBER99, BIO+ (CHARMM27) and OPLS, with their default parameters as implemented in HyperChem software. RHF operators were used for “Spin Pairing” in the case of neutral molecules and cations, and UHF operators for radicals and radical cations. The SCF “Convergence limit” was set at 10-5, without using the “Accelerate convergence” procedure. For geometry optimization and ΔHf calculation, the “Polak-Ribière (conjugate gradient)” algorithm was selected with a RMS gradient of 0.01 kcal/ (Å * mol), the molecules being considered in vacuum (conditions similar to those found in EI-MS detectors). Results and Discussion

The EI-MS spectra for the family of glucose (Glc) derivatives are given as an example for the aldo-hexofuranose class of compounds in Figure 3. Additionally, the spectra for the other 4-bromobutyl (R = C4Br) derivatives are shown in Figure 4. The spectra for decyloxybutyl 2,3:5,6-di-O-isopropyl-idene-d-mannofuranosides (both anomers) taken at 70 eV [62] and for 1,2:5.6-di-O-isopropylidene-α-d-glucofuranose taken at 5 eV [67] were illustrated in previous papers.

Figure 3.

The EI-MS spectra for 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose (top) and 3-O derivatives (towards bottom: but-3-enyl, 4-bromobutyl, 4-(octyloxy)butyl and 4-(decyloxy)butyl)


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Figure 4.

The EI-MS spectra for 4-bromobutyl derivatives of 1,2:5,6-di-O-isopropylidene-α-d-galactofuranose (top) and 2,3:5,6-di-O-isopropylidene-d-mannofuranose (α anomer middle, β anomer bottom)

By operating in positive ion mode, the cations are obtained whose charged centres can be spontaneously stabilized by oxygen lone pair electrons. As can be seen, the m/z = 101 peak [62-67], which corresponds to the 2,2-dimethyl-1,3-dioxolan-4-ylium cation (Figure 5) formed after the homolytic fission [54,73] of the C4-C5 bond, is either the base peak or has a strong intensity in all the given spectra. The intensities of this peak for all the analysed compounds are given in Table I.

Figure 5.

The α-Oxy resonance stabilization in 2,2-dimethyl-1,3-dioxolan-4-ylium oxocarbenium ion (m/z =

101)

Table I

The peak intensities (counts); TIC: Total Ion Current, BP: Base Peak, I101: intensity for m/z = 101 peak, %TIC = I101/TIC·100, %BP = I101/BP·100

Lateral chain (R) Base structure TIC BP I101 %TIC %BP

H (none)

Glc 1065846 156928 156928 15 100 Gal 766260 115624 115624 15 100 α-Man 2843816 411968 378944 13 92 β-Man 35486 4690 4690 13 100

C4

Glc 1244608 222464 159232 13 72 Gal* 10988 516 171 2 33 α-Man 30672 2753 1914 6 70 β-Man 20256 1135 1108 5 98

C4Br

Glc 21060 2136 2136 10 100 Gal 43760 2432 2315 5 95 α-Man 1245380 118944 118944 10 100 β-Man 243807 29736 29736 12 100

C4OC8

Glc 413004 49808 49528 12 99 Gal* 86995 2489 735 1 30 α-Man 157033 8701 8701 6 100 β-Man* 108414 3620 3620 3 100

C4OC10

Glc 4651318 637760 523712 11 82 Gal 121146 7937 7793 6 98 α-Man 2200034 189952 189952 9 100 β-Man 364043 35680 35680 10 100

*poor signal-to-noise ratio. The C4-C5 bond lengths for the molecular radical cations, calculated with the RM1 semi-empirical method, are given in Table II. The force field pre-

optimization was also carried out to generate a variety of starting geometries for the RM1 semi-empirical optimization, in order to minimize the


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possibility for locating structures that correspond to a local, but not a global minimum energy. The additional starting structures were obtained by setting the O4-C4-C5-O5 dihedral (bond torsion) to

0° or 180°, presuming that oxygen lone pairs may be better positioned in this way to stabilize the radical cation (proper orbital overlapping) [12, 19].

Table II

The bond lengths (in Å) for the C4-C5 bond in molecular radical cations (lowest energy C4-C5 long bond conformer in bold)

Lateral chain (R) Base structure RM1 AMBER/RM1 CHARMM/RM1 MM+/RM1 OPLS/RM1 0° 180°

H (none)

Glc 1.545 2.133 2.131 1.545 1.545 1.545 1.538 Gal* 1.536 1.552a 1.536 1.536 1.552a 1.546b 1.548 α-Man* 1.540 1.541 1.541 1.542 1.542 1.537 1.536 β-Man* 1.545 1.544 1.544 1.545 1.544 1.545 1.542b

C4

Glc 2.091 1.539c 2.118 1.541c 1.539c 2.119 1.534 Gal* 1.543c 1.549 1.543c 1.549 1.543c 1.549d 1.543 α-Man 1.536c 1.537c 2.093 1.536c 1.540e 2.111 1.536 β-Man* 1.541c 1.539c 1.541c 1.541c 1.541c 1.548f 1.541b

C4Br

Glc 2.091 2.118 2.115 2.091 2.118 2.117 2.180 Gal* 1.548 1.549 1.549 1.549 1.549 1.549d 1.548 α-Man 2.095 2.096 2.095 2.095 2.096 2.117 1.536 β-Man 2.091 2.091 2.091 2.091 2.091 2.091 1.541b

C4OC8

Glc 2.091 2.117 2.117 2.091 2.117 2.117 2.989 Gal 2.081 2.081 2.081 2.081 1.549 1.549d 2.081 α-Man 2.093 2.093 2.093 2.097 2.093 2.112 1.536 β-Man 2.091 2.091 2.090 2.090 2.091 2.090 1.541b

C4OC10

Glc 2.090 2.117 2.117 2.091 2.117 2.117 2.989 Gal 2.081 2.081 2.081 2.081 1.549 1.549d 2.081 α-Man 2.093 2.093 2.093 2.097 2.091 2.112 1.536 β-Man 2.091 2.091 2.090 2.090 2.091 2.091 1.541b

a long bond located between C2 and C3 (2.091 Å) instead; b H6 proton shift to O1 (1.079-1.108 Å new formed bond length), possibly a distonic cation; c double bond becomes longer (1.402-1.410 Å) instead [20,28,42,74,75]; d complex rearrangement, possibly a distonic cation (see Figure 6); e allylic proton shift to O4 (1.000 Å new formed bond length), possibly a distonic cation; f allylic proton shift to O5 (1.062 Å new formed bond length), possibly a distonic cation; * C4-C5 long bond obtained when starting from C4OC10 derivatives (see text): Gal-H 2.081, α-Man-H 2.100, β-Man-H 2.100, Gal-C4 2.081, β-Man-C4 2.090, Gal-C4Br 2.082 (Å).

Figure 6.

Rearrangement seen for Gal derivatives when starting O4-C4-O5-C5 dihedral (bond torsion) is set to 0° (prior to RM1 optimization); R = C4, C4Br, C4OC8, C4OC10;

newly formed C-O bond is 1.440-1.441 Å long As can be seen from Table II, a long bond [19] was obtained for almost all the molecular radical cations in the ground state, located in the furanose moiety between C4 and C5 (the only exception seems to be β-Man-H, for which the double bond becomes elongated in the lowest energy state). It has a length of 2.081-2.133 Å, as opposed to 1.537-1.543 Å for the neutral molecules. The H4-C4-C5 and the H5-C5-C4 angles have values of 90-95°, which suggests an sp2 geometry with the C4-C5 long bond being almost (but not quite) perpendicular on the plane which contains the other three bonds for each carbon atom (as opposed to 108-112° sp3 angles in

the starting neutral molecules). The other angles are also fairly constant in the series (see Table III), reminding of the D3d point group symmetry for the ethane radical cation in the 2A1g ground state, with a very slight distortion towards a diborane-like C2h structure [14, 26]. Thus, it would appear that the alkyl side chain has little influence over the geometry of the long bond. Some molecular radical cations did not show at first a C4-C5 long bond after RM1 optimization. However, when starting from optimized C4OC10 radical cations, which already possess the C4-C5 long bond, after modifying the lateral chain accordingly and performing the RM1 reoptimization, the long bond remained intact for these exception compounds (see Table II footnotes). In all C4-C5 long bond cases, the radical character is concentrated in the C4 and C5 carbon atoms, but also in adjacent O4 and O5 oxygen atoms (e.g. spin population in DAG-H is 0.415 for C4, 0.214 for C5, 0.179 for O4 and 0.158 for O5), thus revealing that O4 and O5 stabilize the long bond (the electron spin density is delocalized on the O4-C4-C5-O5 framework).


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Table III Some angles (in degrees) for molecular radical cations (values for lowest energy C4-C5 long bond conformers)

Lateral chain (R) Base structure O4-C4-C5 O5-C5-C4 O4-C4-C5-O5

H (none)

Glc 99.7 99.7 1.9 Gal 101.0 100.8 -177.7 α-Man 99.9 100.9 54.5 β-Man 101.6 100.6 54.1

C4

Glc 99.5 100.0 -4.5 Gal 101.0 100.9 -177.8 α-Man 100.0 101.0 54.3 β-Man 101.8 100.9 54.8

C4Br

Glc 99.5 100.0 -4.8 Gal 100.9 100.9 -177.7 α-Man 100.0 101.0 54.3 β-Man 101.6 100.9 54.3

C4OC8

Glc 99.5 100.0 -5.4 Gal 101.0 100.9 -177.7 α-Man 99.9 101.0 54.2 β-Man 101.7 100.8 54.8

C4OC10

Glc 99.5 100.0 -5.0 Gal 101.0 100.9 -177.6 α-Man 100.1 101.1 54.4 β-Man 101.7 100.8 54.7

The enthalpy of formation for the radical cation from the neutral precursor was calculated to be in the 201.361 ÷ 206.274 kcal/mol range for all

compounds, with an average value of 204.082 kcal/ mol. The heat of formation values for all radical cations are given in Table IV.

Table IV ΔHf values (in kcal/mol) for molecular radical cations (lowest energy C4-C5 long bond conformer in bold)

Lateral chain (R) Base structure RM1 AMBER/RM1 CHARMM/RM1 MM+/RM1 OPLS/RM1 0° 180°

H (none)

Glc -67.806 -78.786 -78.784 -67.806 -67.806 -67.806 -70.351 Gal* -63.471 -73.266a -63.471 -63.471 -73.266a -84.659b -70.065 α-Man* -69.695 -69.464 -69.464 -69.894 -69.704 -69.212 -73.133 β-Man* -69.356 -69.143 -69.143 -69.356 -69.143 -69.356 -84.316b

C4

Glc -60.140 -54.832c -60.807 -55.166c -54.946c -60.808 -55.184 Gal* -55.319c -51.472 -56.283c -51.472 -56.283c -56.135d -55.318 α-Man -62.975c -62.575c -63.621 -62.885c -76.109e -61.257 -54.509 β-Man* -63.144c -69.613c -63.143c -63.144c -62.970c -79.926f -66.691b

C4Br

Glc -84.453 -84.967 -84.966 -84.453 -84.966 -84.967 -79.692 Gal* -76.660 -76.513 -76.513 -76.512 -76.513 -80.841d -76.661 α-Man -88.316 -88.315 -88.316 -88.314 -88.315 -85.986 -79.580 β-Man -88.092 -88.093 -88.093 -88.092 -88.092 -88.092 -90.105b

C4OC8

Glc -157.569 -158.238 -158.232 -157.567 -158.234 -158.235 -155.122 Gal -160.412 -160.404 -160.409 -160.403 -149.051 -153.605d -160.412 α-Man -161.191 -161.190 -161.194 -161.133 -161.188 -158.866 -152.109 β-Man -161.132 -161.133 -161.129 -161.128 -161.134 -161.125 -164.119b

C4OC10

Glc -167.564 -168.225 -168.223 -167.562 -168.218 -168.229 -165.117 Gal -170.408 -170.397 -170.405 -170.398 -159.048 -163.603d -170.408 α-Man -171.184 -171.181 -171.188 -171.126 -172.149 -168.858 -162.105 β-Man -171.125 -171.129 -171.124 -171.122 -171.128 -171.115 -174.117b

a-f same as for Table II; * C4-C5 long bond obtained when starting from C4OC10 derivatives (see text): Gal-H -80.355, α-Man-H -81.453, β-Man-H -81.776, Gal-C4 -62.833, β-Man-C4 -63.673, Gal-C4Br -87.395 (kcal mol-1). Some entries from Table IV show that the C4-C5 long bond structures are energetically favoured when compared with other forms of radical cations. Thus, the C4-C5 long bond structures generally lie a few kcal/mol lower than structures with normal length bonds (e.g. 8.435 kcal/mol for Glc-H, 10.290 kcal/mol for Gal-H, 8.320 kcal/mol for

α-Man-H and 12.420 kcal/mol for β-Man-H). Also, for but-3-enyl derivatives, some results have indicated that the double bond would become elongated, followed by a twisting of the double bond geometry with a dihedral value of 21 - 36° [20, 28, 42, 74, 75].


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If we count the long bond structures in Table II, we notice that the best method for localizing the long bond energy minima seems to be CHARMM/RM1. Thus, the following order was established for the force field pre-optimization usefulness (the number of long bond hits, from a total of twenty structures, are given in parenthesis):

CHARMM (14) > AMBER (12) > MM+ (11) > OPLS (9)

If an additional energy criteria is to be implemented, namely that the difference between the considered long bond structure and the absolute minimum long bond structure to be less than 0.1 kcal/mol, we get the following order:

CHARMM (13) > AMBER (11) > OPLS (9) > MM+ (7)

Thus, the best method remains CHARMM/RM1 (65% hits), followed closely by AMBER/RM1. This fact was expected, being known that CHARMM and AMBER force fields give good results for carbo-hydrates [76]. The worse method proved to be the one in which the initial O4-C4-O5-C5 dihedral was set to 180 degrees (which gave 10% hits, probably also because unwanted proton shifts). If the same dihedral was initially set at 0 degrees, the results were no better the situation when the MM+ force field was used. For comparative purposes, the RM1 C4-C5 bond length and heat of formation data for neutral molecules is also given in Table V. Known literature values for similar compounds, obtained

by X-ray crystal diffraction, are very close to the calculated values from this paper [77, 78]. The BDE [79] can be roughly estimated from Table IV data for Glc-C4OC8 and Glc-C4OC10. As can be seen in Table II, the distance between C4 and C5 for these compounds increases, after RM1 optimization, to almost 3 Å when the initial O4-C4-C5-O5 angle is set to 180°. The obtained system can thus be considered to contain the two fragments resulted from the C4-C5 bond breaking, covalent interactions between these two atoms being lost. Using the minimum heat of formation values for C4-C5 long bond structures and also for the 180° initial O4-C4-C5-O5 starting dihedral cases, we obtained 3.116 kcal/mol (Glc-C4OC8) and 3.112 kcal/mol (Glc-C4OC10) for BDE, so the C4-C5 bond can be broken relatively easy. This observation agrees well with the fact that the molecular radical cation is barely visible in the mass spectra, or it is even missing at all [67]. Also, HyperChem clearly indicates in the 180° initial O4-C4-C5-O5 starting dihedral cases for these two compounds that the charge is retained by the 2,2-dimethyl-1,3-dioxolan-4-ylium fragment, while the radical character is mostly localized at C4 (and some at O4), in agreement with the complete disruption of the covalent interactions between the two fragments [23]. This observation is also in accordance with EI-MS data, where the [M-101]+ fragment has much lower intensity in di-O-isopropylidene aldohexo-furanose species by comparison with the m/z 101 peak [62-67].

Table V Neutral molecules bond lengths (for C4-C5 bond) and ΔHf values

Lateral chain (R) Base structure Bond length (Å) ΔHf (kcal/mol)

H (none)

Glc 1.538 -284.534 Gal 1.537 -283.529 α-Man 1.539 -287.727 β-Man 1.540 -284.788

C4

Glc 1.538 -264.938 Gal 1.543 -266.852 α-Man 1.538 -268.057 β-Man 1.540 -265.034

C4Br

Glc 1.538 -291.223 Gal 1.543 -293.147 α-Man 1.538 -294.405 β-Man 1.540 -291.519

C4OC8

Glc 1.538 -362.418 Gal 1.543 -364.938 α-Man 1.538 -365.516 β-Man 1.540 -362.564

C4OC10

Glc 1.538 -372.415 Gal 1.543 -374.934 α-Man 1.538 -375.512 β-Man 1.540 -372.560

We have also tried to estimate the BDE values for C4-C5 bond using the enthalpies of formation [79]

for the fragments resulted after its homolysis (BDEHO) or the alternative heterolysis (BDEHE) [54,


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73]. All the calculated values are given in Table VI; the obtained enthalpy of formation for the 2,2-dimethyl-1,3-dioxolan-4-ylium (m/z 101) fragment was 98.756 kcal/mol, while for the 2,2-dimethyl-1,3-dioxolan-4-yl radical it was -78.755 kcal/mol. The BDEHO values calculated from Table VI are five times larger than those estimated from Table IV. This would suggest that the systems which show a C4-C5 bond length of about 3 Å (Glc-C4OC8 and Glc-C4OC10) are not completely dissociated, and each of them can be considered as

an ion neutral complex. Also, the calculated values for BDEHO seem to be somewhat larger than those for BDEHE. However, this was not confirmed from EI-MS experiments, where m/z 101 ion abounds while the remaining fragment (e.g. m/z 159 if R = H in Figure 2) has low intensity for all compounds, and thus homolysis clearly predominates. The RM1 semi-empirical method may not be sufficiently accurate, or the parameters used may not be optimal to predict the right mechanism in this case. Also, the entropic change of the system was not calculated.

Table VI ΔHf and BDE values (in kcal/mol)

Lateral chain (R) Base structure Radical cation [M-101]· BDEHO [M-101]+ BDEHE BDEHO-BDEHE

H (none)

DAG -78.786 -164.789 12.753 11.690 11.721 1.032 DAGal -80.355 -164.789 14.322 11.690 13.290 1.032 DAM-α -81.453 -167.057 13.152 9.496 12.194 0.958 DAM-β -81.776 -164.105 16.427 11.893 14.914 1.513

C4=


C4Br


C4C8

DAG -158.238 -243.209 13.785 -69.408 10.075 3.710 DAGal -160.412 -243.212 15.956 -69.197 12.460 3.496 DAM-α -161.194 -244.899 15.051 -71.713 10.726 4.325 DAM-β -161.134 -241.994 17.896 -69.133 13.246 4.650

C4C10

DAG -168.229 -253.206 13.779 -79.397 10.077 3.702 DAGal -170.408 -253.204 15.960 -79.193 12.460 3.500 DAM-α -172.149 -254.895 16.010 -81.708 11.686 4.324 DAM-β -171.129 -251.991 17.894 -79.127 13.247 4.647

Table VII

The bond lengths (for the C4-C5 bond) and ΔHf values in the case of molecular radical cations of other mannose derivatives (α/β)

N* Without spacer With oxybutyl spacer C4-C5 bond length (Å) ΔHf (kcal/mol) C4-C5 bond length (Å) ΔHf (kcal/mol)

1 2.095a/2.092a -76.496a/-76.581a 2.093/2.090 -125.538/-125.446 2 2.091b/2.088c -84.013b/-84.212c 2.093/2.091 -131.100/-131.028 3 2.093/2.091 -87.765/ -87.807 2.093/2.091 -136.232/-136.166 4 2.092/2.092 -92.773/-92.832 2.093/2.091 -141.193/-141.129 5 2.092/2.092 -97.807/-97.871 2.093/2.091 -146.203/-146.143 6 2.091b/2.088d -104.165b/-104.403d 2.093/2.091 -151.198/-151.137 7 2.092/2.092 -107.816/-107.895 2.093/2.091 -156.194/-156.136 8 2.092/2.092 -112.815/-112.898 2.093f/2.091e -161.194f/-161.134e 9 2.092/2.092 -117.814/-117.899 2.093/2.091 -166.186/-166.130

10 2.093/2.092 -122.811/-122.900 2.091e/2.091g -172.149e/-171.129g 12 2.093/2.092 -132.806/-132.897 2.093/2.090 -181.179/-181.117 14 2.092/2.092 -142.800/-142.888 2.093/2.091 -191.171/-191.111 16 2.092/2.092 -152.788/-152.886 2.093/2.091 -201.167/-201.098 18 2.093/2.092 -162.775/-162.876 2.093/2.091 -211.160/-211.096 20 2.093/2.092 -172.767/-172.859 2.093/2.091 -221.153/-221.093 30 2.092/2.092 -222.765/-222.847 2.093/2.091 -271.137/-271.074

*number of carbon atoms in the alkyl chain; a C4-C5 long bond obtained when starting from Man-C4OC10 derivatives; b O4-C4-C5-O5 angle initially set at -90 degrees; c O4-C4-C5-O5 angle initially set at 90 degrees; d O4-C4-C5-O5 angle initially set at 0 degrees; e OPLS force field pre-optimization; f CHARMM force field pre-optimization; g AMBER force field pre-optimization.


561

To further study if the lateral chain has any influence over the properties of the long bond, a larger series of mannose derivatives was considered. Thus, the decyl chain in Man-C4OC10 was replaced for RM1 calculations with other alkyl fragments, ranging from methyl to nonyl, and also with dodecyl, tetra-decyl, hexadecyl, octadecyl, eicosyl and triacontyl chains. Variants without the butoxy spacer (with the alkyl chain directly attached to O1) were also modelled. Calculations were made for both anomers. All these mannose derivatives behaved as expected, similar with Man-C4OC8 and Man-C4OC10 species (see Table VII). Although from experimental EI-MS data the discussed C4-C5 bond breaking is pretty obvious for aldohexofuranose di-O-isopropylidene derivatives, the corresponding long bond does not always appear when modelling these compounds, as can be seen in Table II. Instead, one C2-C3 long bond (Figure 7) was sometimes observed in 1,2:5,6-di-O-isopropyl-idene-α-d-galactofuranose. This is, however, difficult to confirm in the EI-MS spectra because the product of such breaking would have the same m/z as the initial radical cation molecule (m/z = 260). The possible fragments that would account for such breaking could be the ones spotted at m/z 100, 115 or 143, which have low intensity (these fragments would also imply a second fragmentation near the tetrahydrofuran oxygen, together with a hydrogen radical lose for the last two). A C2-C3 bond fission was also proposed in literature for 1,2:3,5-di-O-isopropylidene-α-d-xylo-furanose, to explain the m/z = 113 peak in its EI-MS spectrum [63].

Figure 7.

The comparison between the C2-C3 long bond structure (left) and the C4-C5 long bond structure

(right) for 1,2:5,6-di-O-isopropylidene-α-d-galacto-furanose (carbon - light blue, oxygen - red,

hydrogen - white) It is also worth mentioning that similar compounds like 1,2:3,4-di-O-isopropylidene-α-d-galactopyranose, 2,3:4,5-di-O-isopropylidene-β-d-fructopyranose, 1,2:4,5-di-O-isopropylidene-β-d-fructopyranose and 2,3:4,6-di-O-isopropylidene-α-l-sorbofuranose were computationally determined to possess a long bond in their radical cation ground state, located in the sugar moiety in various locations. These compounds, along with the PM7 semi-empirical

method results (which also confirms the long bond), will be discussed in future papers.

Conclusions

The relatively weak C4-C5 long bond obtained in silico in the studied series of compounds is a strong argument regarding the genesis of the intense m/z 101 peak observed in the EI-MS analysis of di-O-isopropylidene aldohexofuranose structures. All the considered glycoderivatives show such a long bond energy minimum as radical cation, and the CHARMM force field was found to give the best results when used for pre-optimization, before the RM1 semi-empirical method was applied. A single case was obtained in which the absolute energy minimum was found when the radical character was localized in the double bond. Also, long bonds seem to be a ubiquitous feature in the radical cations of monosaccharide di-O-isopropylidene derivatives. Recognition of such long bonds has implications in both gas state (e.g. EI-MS) and solution (e.g. cycloaddition) chemistry of radical cations [19], while studies of the structures of di- and poly-functional molecules are of relevance in fields like biological chemistry and pharmaceuticals synthesis and analysis. Acknowledgement

This work was supported by the Romanian National Authority for Scientific Research (CNCS-UEFISCDI) through project PN-II-PCCA-2011-142 and POSCCE 1854-(48749)-2015-677. The authors would like to thank Prof. PhD. Eng. Nicolae Dincă and Prof. PhD. Mircea Mracec for access to HyperChem software and for valuable discussions. References

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computational search for long bonds in radical cations of sugars 1

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